Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial

Guidelines recommend that patients receiving warfarin undergo international normalized ratio (INR) monitoring every 4 weeks. To investigate whether assessment of warfarin dosing every 12 weeks is as safe as assessment every 4 weeks. Noninferiority randomized trial. The randomization schedule (in a 1:1 ratio) was computer-generated, and allocation was concealed until the database was locked by using a centralized schedule. Patients, study and clinical personnel, adjudicators of clinical events, and the study statistician were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00356759) SETTING: Single center in Hamilton, Ontario, Canada. 250 patients receiving long-term warfarin therapy, whose dose was unchanged for at least 6 months; 226 completed the study. Dosing assessment every 12 weeks (n = 124) compared with every 4 weeks (n = 126) for 12 months. Patients in the 12-week group were tested every 4 weeks; sham INRs within the target range were reported for two of the three 4-week periods. Percentage of time in the therapeutic range (primary outcome) and number of extreme INRs, changes in maintenance dose, major bleeding events, objectively verified thromboembolism, and death (secondary outcomes). The percentage of time in the therapeutic range was 74.1% (SD, 18.8%) in the 4-week group compared with 71.6% (SD, 20.0%) in the 12-week group (absolute difference, 2.5 percentage points [1-sided 97.5% upper confidence bound, 7.3 percentage points]; noninferiority P = 0.020 for a 7.5-percentage point margin). Fewer patients in the 12-week group than in the 4-week group had any dose changes (37.1% vs. 55.6%; absolute difference, 18.5 percentage points [95% CI, 6.1 to 30.0 percentage points]; P = 0.004). Secondary outcomes did not differ between groups. Patients in the 12-week group had testing and contact with clinic staff every 4 weeks. The study was conducted at a single center and used surrogate outcomes. Assessment of warfarin dosing every 12 weeks seems to be safe and noninferior to assessment every 4 weeks. A comparison of INR testing, patient contact, and warfarin dose assessment every 12 weeks versus every 4 weeks is necessary before INR testing every 12 weeks can be routinely recommended for practice. Physicians' Services Incorporated Foundation.